This application focuses on the potential for using ex vivo expanded autologous regulatory T cells (Tregs) in the treatment of autoimmune diseases. The central theme is that Tregs provide important protection against autoimmunity. Based on this theme, the central hypothesis is that Treg therapy may be a safe and effective approach to the treatment of diverse autoimmune diseases. To address this hypothesis, we propose two complementary projects. One project will examine Treg therapy in an antigen-non-specific autoimmune disease (systemic lupus erythematosus)(SLE), and one will examine Treg therapy in an antigen-specific autoimmune disease (pemphigus vulgaris)(PV). The selection of these two diseases affords us the following important opportunities: (i) to examine whether this therapeutic approach is generally applicable across clinically distinct autoimmune diseases; (ii) to compare safety, efficacy, and mechanism of action across both antigen-specific and antigen-non-specific autoimmune diseases; (iii) to compare polyclonal and antigen-specific Treg therapy in the same disease (PV); and (iv) to examine the same target tissue (skin) in both lupus and PV disease. The specific aims are: Primary Project - Conduct a phase l-ll development program designed to test the feasibility, safety, and potential efficacy of Treg therapy in patients with cutaneous manifestations of lupus. Alternate Project - Conduct a phase l-ll development program designed to compare autologous polyclonal versus enriched antigen-specific Treg therapy in patients with PV. Through these projects, we aim to demonstrate the presence and persistence of transferred Tregs in blood and target tissue; perform T cell receptor sequencing to determine whether infused Tregs proliferate; assess biomarkers in blood and skin; and generate efficacy data to lay the foundation for eventual pivotal trials.